6alpha methyl, 9alpha f, 17alpha oh 1, 4 pregnadiene compounds



United States Patent 60: METHYL, 9aF,17a 6H 1,4 PREGNADIENE COMPOUNDS Frank H. Lincoln, Jr., Kalamazoo, William P. Schneider, Kalamazoo Township, Kalamazoo County, and George B. Spero, Kalamazoo, Mich, assignors to The Upjohn Company, Kalan'iazoo, Mich., a corporation of Michigall No Drawing. Application May 17, 1957 Serial No. 659,748

3 Claims. (Cl. 260-397.45)

and S. N. 623,780, filed November 23, 1956.

The new compounds and the process of the present invention are illustratively represented by the following formulae:

IV 0113 III a :0 on 0113K; o: 1 CH3 V wherein R is an organic radical 'such as" methyl, ethyl, propyl, tolyl, naphthyl, or the like, with methyl preferred.

"ice

The process of the present inventon comprises treating 6 methyl 5 9oz fluoro 1lfl,l7a,2l trihydroxy 1,4- pregnadiene-3,20-dione [1-dehydro-6-methyl-9a-fluorohydroc'ortisone (1)] with an organic sulfonyl halide such as methanesulfonyl chloride, toluenesulfonyl chloride, toluenesulfonyl bromide, benzenes'ulfonyl chloride, aand B-naphthylsulfonyl chloride, or the like, to obtain the corresponding ester (II), a 2l-alkylor 2l-arylsulfonate' of 6 methyl 9a fluoro l1[3,l7a,2l 5 trihydroxy 1,4-- pregnadiene-3,20-dione; treating the thus produced 2lalkylor arylsulfonate of 6-rnethyl-9a-fluoro-11B,17a,21' trihydroxyl,4-pregnadiene-3,ZO-dione with sodium iodide in acetone solution to obtain 6-methyl-9a-fluoro-llfi,17adihydroxy-Zl-iodo-1,4-pregnadiene-3,20 dione (III); treating the thus obtained 6-methyl-9a-fiuoro-11/8,17a-dihydroxy-Zl-iodo-l,4-pregnadiene-3,20-dione with a reducing agent such as sodium thiosulfate, sodium bisulfite, potassium bisulfite, or the like, in an aqueous organic solvent mixture to obtain 6-methyl-9a-fiuoro-ll 3,l7a-dihydroxy-1,4-pregnadiene-3,20-dione (IV) and if desired oxidizing the thus obtained 6-methy1-9a-fluor0-1lfl,17oc,dihydroxy-l,4-pregnadiene-3,20-dione with chromic anhydride, N-bromoacetamide, N-bromosuccinimide, or the like, to give 6-methyl-9a-fluoro-l7u-hydroxy-1,4-pregnadiene-3,11,20-trione (V). p 7

It is an object of the instant invention to provide 6- methyl a fluoro 1113,17oc dihydroxy 1,4-pregnadiene 3,20 dione and 6 methyl 9oz fluoro 17ahydroXy-l,4-pregnadiene-3,l1,20-trione and, in particular, the 6a epimers, 60c methyl 9a fluoro 115,170;- dihydroxy 1,4 pregnadiene 3,20 dione and 6amethyl 90c fiuoro 17a hydroxy 1,4 pregnadiene- 3,11,20-trione. It is anotherobject of the instant invention to provide a process for the preparation of 6-methyl- 9a fluoro 11 3,1704 dihydroxy 1,4 pregnadiene 3,20- dione and 6-' methyl 90c fluoro 17oz hydroxy 1,4- pregnadiene-ESJ1,20-trione and the 2l-iodo analogues thereof, especially 6-methyl-9 ;-fluoro-1l 3,l7a-dihydroxy- 2l-iodo-l,4-pregnadiene-3,20-dione. Other objects of'this invention will be apparent to those skilled in the art to which this invention pertains. v

The novel 6u-methyl-9a-fiuoro-11B,l7a-dihydroxy-1,4- pregnadiene-3,20-dione, the 6u-methyl-9a-fluoro-17a-hydroxy-l,4-pregnadiene-3,l1,20-trione possess a high order of physiological activity, and possess activity spectra different from the adrenocortical hormones found in nature such as hydrocortisone and cortisone especially in their effect on mineral and Water metabolism. These compounds cause a loss of salt and water, and this activity makes them especially valuable in the management of chronic congestive heart failure and in the treatment of cirrhosis of the liver, the nephrotic syndrome and the treatment of eclampsia and preeclampsia. The novel synthetic corticosteroid hormones of the present invention possess also anti-inflammatory, glucocorticoid, uterine, ovarial and adrenal growth-depressional, and adrenocorticoid activity. The anti-inflammatory activity is especially noticeable in all the steroids of the present invention. The 6,8-epimers, 6B-methy1-9o c-fluoro-ll fl,17a-dihydroxy- 1,4-pregnadiene-3,ZO-dione and 6fi-methyl-9a-fluoro-l7ehydroxy-1,4-pregnadiene-3,11,20-trione possess the same either polyethylene glycol 4000 or 6000 as a carrier or lac tose and/or sucrose as a diluent. The novel 6d-methyl- 9a fluoro 11 3,17 dihydroxy 1,4 pregnadiene 3 ,20- dione and 6oa-methyl-9a-fluoro-l 7ouhydroxy-l,4 pregna- *tlie'ne-3,l1,20-trione are useful for topical application as ointments, lotions, jellies, creams, suppositories, bougies,

aqueous suspensions etc. Examples of advantageous topical compositions are given below. While the examples below are to the 6a-methyl-9u-fluoro-11fl,l7a-dihydroxy- 1,4-pregnadiene-3,20-dione and 6a-methyl-9a-fluoro-l7uhydroxy 1,4 pregnadiene 3,11,20 trione, equivalent amounts of 6B-methyl-9a-fluoro-11,3,17a-dihydroxy-L4- droxy-l,4-pregnadiene-3,11,20-trione and of other 6-lower-alkyl and phenyl homologues of the compounds of this invention are substitutable therein.

,A dermatological and ophthalmic ointment has the following composition:

, Lbs. Wool fat, U. S. P a 100 Mineral oil U. S. P 125 6a methyl 9a fluoro- 1113,1706 dihydroxy- .1,4 pregnadiene 3,20 dione (micronized) 0.5

iWhite petrolatum, U. S. P 500 Incorporation of an antibiotic in the ointment, especially neomycin sulfate, has therapeutic advantages; each active ingredient potentiating and supplementing the useful properties of the other. Such an ointment is as In place of, or in addition to neomycin sulfate, other antibiotics such as bacitracin, circulin, polymyxin B sulfate, gramicidin, streptomycin sulfate, dihydrostreptomycin sulfate, oxytetracycline, chlorotetracycline, tetracycline, chloramphenicol and the sulfonamides can be used in conjunction with the steroids of the present invention for preparations such as the above ointments.

, The 6 methyl 90c fluoro l1[3,l7ot dihydroxy 21- iodo-l,4-pregnadiene-3,20-dione is important as an intermediate for the production of 6-methyl-9ct-fluoro-l15,17adihydroxy 1,4 pregnadiene 3,20. dione as shown in Example 3.

In carrying out the process of therinstant invention,

1 dehydro- 9oz fluoro 6 methylhydrocortisone (6amethyl 9a fluoro 11fi,17a,21 trihydroxy 1,4 pregnadiene.- 3,20 dione. or 6B methyl 90c fluoro- 1lfi,17a,21 trihydroxy 1,4 pregnadiene -.3,20 dione) is treated with an acid halide of a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, aor fi-naphthanesulfonic acid, or the like, with .methanesulfonic acid halides especially methanesulfonyl chloride preferred. In the preferred embodiment of the instant invention the steroid is reacted with the alkylor arylsulfonyl halide, in solution in a solvent, such as for example, pyridine, benzene, toluene, or the like, at a temperature between minus ten and plus thirty degrees centigrade, providing that at the lower temperature the reaction mixture has not solidified. Pyridine as solvent "and a temperature between minus ten and plus ten degrees centigrade is preferred. The time of reaction is usually between thirty minutes and twenty four hours, after which the product, 6-methyl-9u-fluoro-l1;3,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione 2l-alkylor .arylsulfonate is removed in conventional manner, for example, by evaporating the solvent until a dry residue is obtained or by extracting the material from an aqueous solution. For

3,20 dione For .the purpose of producingthe final product, it is v 4 unnecessary to purify the thus obtained 2l-arylor 21- alkylsulfonate, and the crude steroid sulfonate ester is used for the production of 6-rnethyl-9a-fluoro-11,8,17adihydroxy 21 iodo 1,4- pregnadiene 3,20 dione.

The 21-iodo compound is prepared by reacting the alkylor arylsulfonate of 6-methyl-9u-fiuoro-ll;8,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione with sodium or potassium iodide in acetone solution. A molar excess of sodium iodide (three to twenty moles of sodium iodide per mole of steroid) is generally preferred for this reaction and the reaction mixture containing 6-methyl-9a-fluoro-115,1711,- 21 trihydroxy 1,4 pregnadiene 3,20 dione 21- alkylor arylsulfonate and sodium iodide in acetone is heated to reflux for a period of three or four minutes to half an hour. The thus produced 6-methyl-9ot-fluoro- 115,170: dihydroxy 21 -.iodo 1,4 pregnadiene- 3,20-dione is isolated by evaporating the solvent. For the subsequent reaction it is unnecessary to purify the thus obtained 6 --rnethyl 9a fluoro 11,8,l7a dihydroxy- 21-iodo-l,4-pregnadiene-3,20-dione. s

In order to obtain 6 n1ethyl-9a-fluoro-115,17a-dihydroxy 1,4 pregnadiene 3,20 dione, the crude 6- methyl fluoro 115,17a dihydroxy 21 --iodol,4-pregnadiene-3,20 dione is reacted with a reducing agent such as sodium or potassium thiosulfate, sodium bisulfite, or the like. In the preferred embodimentof theinvention, the crude 6-rnethyl-9a-fluorol113,17a-dihydroxy-2l-iodo-l,4-pregnadiene-3,20-dione is slurried in acetic acid, and thereto is added the aqueous solution of.

sodium or potassiumthiosulfate, bisulfate, or the like, and the mixture stirred at room temperature for a period of ten minutes to two hours. The product is isolated from the aqueous reaction mixture by conventional methods such as filtration or extraction with a water-immiscible organic solvent, such as ether, benzene, methylene chloride, ethylene chloride, carbon tetrachloride, chloroform, hexane, heptane, or the like, and evaporating the extracts. Purification of the thus obtained 6-rnethyl-9a-fluoro- 11,3,17a-dihydroxy-1,4-pregnadiene-3,ZO-dione is carried out by conventional means such as recrystallization from ether, acetone, methanol, ethanol, Skellysolve B hexane, mixtures thereof, or the like; or by chromatography.

The oxidation of 6-methyl-9a-fluoro-1lfl-lh-dihydroxy 1,4-pregnadiene-3,ZO-dione is generally carried out in conventional manner such as, for example, oxidizing the 6 methyl 9a fluoro 115,170: dihydroxy 1,4- pregnadiene-3,20-dione in acetic acid solution with chromic anhydride using a calculated amount of chromic anhydride or a slight excess such as from ten to thirty percent excess above the calculated amount; or oxidizing the 6 methyl 9oz fluoro 1l;3,17u dihydroxy 1,4- pregnadiene-3,20-dione with a N-haloacidamide or N- haloacidimide, such as N-bromoacetamide, N-chlorosuccini-mide, N-bromosuccinimide in pyridine, dioxane, or other solvent solutions. After termination of the oxidation, the oxidant is generally destroyed such as by addition of methyl alcohol or ethyl alcohol, when chromic acid was used, or an alkali bisulfite when either chromic acid or N-bromosuccinimide and other N-haloacylamides were used. Thereafter, the product 6-methyl-9a-fiuoro- 17a-hydroxy-1,4-pregnadiene-3,11,20-trione is obtained by conventional means such as extraction with water-immiscible solvents, for example, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, ether, benzene, toluene, or the like, or by chromatography, if deemed necessary.

The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

EXAMPLE 1 6a-methyl-9u-fluor0-1 1,9,1 7a,21 -zrihydroxy-1 ,4-pregnadiene-3,20- dione 21 -metharzesulfonate I A solution was prepared containing 250 milligrams of l dehydro 6a methyl-9a-fluorohydrocortisone l George The mixture was then filtered, the precipitate washed with water, and dried to give 197' milligrams of crude I as methyl 9a fl'uoro-l15,17a,2l-trihydroxy-lA-pregnadierie-3,20dione ZI-methanesulfon'ate of melting point 165 to 185 de rees centigrade. v

QprQgnadiene-iZO-diOne The crude 197 milligrams of I'nethanesulfonate of 6a-methyl-9ot-fiuoro 11B,17ot,2l trihydroxy 1,4 pregnadiene-3,20-dione of Example lwas dissolved in five milliliters of acetone and treated with a' solution of 197 milligrams of sodium iodide in five milliliters of acetone;

The mixture was heated under reflux" with stirring for v a period of fifteen minutes. -The heating was then discontinued and-the mixture concentrated to dryness at reduced pressure to give 6a-methyl-9cr-fiuoro-l113,171 dihydroxy-Z l-iodo- 1 ,4-pregnadi'ene-3 ,ZO-diQne.

I I EXAMPLE 3" 6oc-methyl-9a-flu0ro 11fi,1'7u-dihydr0xy-1,4-preghadie'ne-3,20-dione The crude 6a-methyl-9wfluoro-11B,17a-dihydr xy-21- iodo-1,4-pregnadiene-3,20-dione was slurried with five milliliters of acetic acid and stirred for a period of 45 minutes. Thereafter was added a solution of 250 milligrams of sodium thiosulfate pentahydrate in five milliliters of water causing the iodine color to disappear. Additional water was added (thirty milliliters) and the reaction mixture Was filtered. The resulting solid precipitate was washed with water and dried to give 146 milligrams of crude 6a-m'e'thyl-9d-fiuoro-1lfl,l7et-dihydroxy-1,4-pregnadiene-3,20 dione.

The crude material was then chromatographed by dissolving 120 milligrams of 6ct-1T1'3thyl-9oC-fluOI'd-1l,17ot dihydroxy-1,4-pregnadiene- 3,20-dionein 300 milliliters of methylene chloride and: allowing the thus obtained solution to be absorbed by a chromatographic column containing ten grams of Florisil anhydrous magnesium silicate. The column was developed taking fractions of twenty milliliters each as follows:-

TABLE 1 Fraction Solvent Skellysolve IB-hexane-% acetone. Skellysolve B-hexane-% acetone. 4 Skellysolve B-hexane-15% acetone. Skellysolve B-hexane-% acetone. Skellysolve B-hexane-30% acetone. Acetone. a

A mixture was prepared containing 0.3 gram of 60c methyl Qa-fluoro 11fi,17oc dihydroxy 1,4 pregnadiene-3,20-dione, 100 milligrams of chromic anhydride',

ten milliliters of glacial acetic acid and one-half milliliter of Water. This mixture was stirred and thereupon maintained for eight hours 'at room temperature. There after the mixture was poured into fifty milliliters of: ice water, neutralized by the addition of dilute sodium hydroxide and the thus obtained precipitate collected on a filter'and recrystallized three times from ethyl acetate arid' skellys'olve B hexanes to give 6ct-1nethyl-9e-fluoro-- 171x-hydroxy-1,4 pregnadiene-3 ,1 1,20-trione.

.. EXAMPLE 5 v In the same manner shown in Example 1, treating,

other l-dehydro-6a-alkyl-9ot-fluorohydrocortisones and 1-dehydro-6a-alkyl-9a-fluorocortisoneswith the chlorides or bromides of toluenesulfonic acid, methanesulfonic-acid and other organic sulfonic acids,- give the corresponding 21-toluene-sulfonate, the ZI-methanesulfonate, or the like, of the corresponding l-dehydro 6a-alkylhydrocortisone and 1-dehydro-6a-a1kyl-9a-fluorocortisone wherein the alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, phenyl, or the like. I

Treating the thus obtained 21-toluenesulfonate, 21-- methanesulfonate or other 21-alkylor 2l-arylsulfonates of 1-dehydro-6oc-alkyl-9u-fluorohydrocortisone and 1-de hydro-6a-alkyl-9o -fiuorocortisone or the l-dehydro-fiaaryl analogues thereof with sodium or potassium iodide in acetone at elevated temperature, usually at reflux temperature, yieldsthe corresponding ,21-iodo compound such as, for example, 6ot-BthYl-9oc-flll0lO-l 1B,l7u-dihydroxy- 21-iodo-1,4-pregnadiene-3,20-dione, Gu-pIOpYl-Qa-flUOIO- 1lfl,17a-dihydroxy-2l-iodo-l,4-pregnadiene 3,20 dione; 6a-isopropyl-9u-fluoro-1l-fl,l7a-dihydroxy 21 iodo-1,4- pregnadiene-3,20-dione, 602-bl1iYl-9or-fill0lO-l119,17a-dlhydroxy-2l-iodo-1,4 pregnadiene 3,20 dione, a isobutyl- 9u-fluoro-11fi,17u-dihydroxy-2l-iodo 1,4 pregnadiene- 3,20-dione, 6a-pentyl-9a-fiuoro 1113,1741 dihydroxy 21-. iodo-1,4-pregnadiene-3,ZO-dione, 60c phenyl 9o: fiuoro- 11B,17u-dihydroxy-21-iodo-1,4-pregnadiene 3,20 dione, 6a-methyl-9a-fluoro 17u-hydroxy-21 iodo 1,4 pregnadiene-3,11',20-trione, 6 xethyl-9a-fiuoro-l7a-hydroxy 2liodo- 1 ,4 pregnadiene-3,1 1,20-trione, 6rx-propyl-9a-fluoro l7m-hydroxy-2l-iodo 1,4 7 pregnadiene 3,11,20 trione, 6or-isopropyl-9oi-fluoro-l7t -hydroxy-2l-ioclo-1,4 pregnadiene-3,11,20-trione, 6a -butyl-9or-fiuoro-17a-hydroxy-2 1- iodo-1,4-pregnadiene 3,11,20 trione, 6oz isobutyl 9afluoro-l7a-hydroxy-2l iodo 1,4 pregnadiene 3,11,20 trione, 6a-pentyl-9a-fluoro-l7a hydroxy 21 iodo 1,4- pregnadiene-3,11,20-trione, 60c hexyl- -.fluoro 17ahydroXy-Zl-iodo 1,4 pregnadiene g 3,11,20 trione, 6aphenyl-9u-fluoro-l7a-hydroxy-2l-iodo 1,4 pregnadiene 3,11,20-trione, and the like.

Treating the thus obtained oa-alkyl-9 -fiuoro-l15,174

dihydroxy-21-iodo-1,4-pregnadiene-3,ZO-diones and 6aalkyl 9a-fluoro-l7a-hydroxy-21 iodo 1,4 pregnadiene- 3,1l,20-triones with a reducing agent, such as zinc in acetic acid, sodium bisulfite, sodium or potassium thiosulfate produces the corresponding 6oc-alkyl-9'or-fluoro- 1 1 8,17a-dihydroxy-1,4-pregnadiene 3,20 diones and 6a; alk'yl-9a-fluor0-l7a-hydroxyl,4 pregnadiene 3,ll,20 triones wherein the alkyl groupis ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, or aryl such as phenyl, or

i the like.

EXAMPLE 6 3,20-di0n'e A mixture of one gram of owniethyl-l1p,l7a-dihydroxy-1,4-pregnadiene-3,20-dione, 650 milligrams of N- bromo-acetamide and six milliliters of pyridine were stirred in the dark for a period of thirty minutes. The mixture was cooled in 'an ice-water bath and a stream of sulfur dioxide was directed onto the surface of the stirred 'mixture until a negative potassium iodide-starch test was triene-3,20-dione was dissolved in twenty milliliters of methylene chloride and thereto was added a solution of one milliliter of 71 percent perchloric acid in ten milliliters of water and 200 milligrams of N-bromoacetamide in fifty milliliters of tertiary butyl alcohol. The solution was maintained at room temperature for fifteen minutes and then mixed with a solution of 0.3 gram of sodium sulfite in twelve milliliters of water. The mixture was distilled at reduced pressure until the residual solution became cloudy. The product was then precipitated by the addition of 100 milliliters of a mixture of ice-water. The white crystalline precipitate was filtered, washed with water and then dried and recrystallized from a mixture of acetone and Skellysolve B hexane hydrocarbons to give 6ot-methyl-9wbromo-11 3,17a,dihyd.roxy-1,4-pregnadiene-3,20-dione.

A mixture of 0.45 gram of 6a-methyl-9a-bromo-11B, l7a-dihydroxy-l,4-pregnadiene-3,ZO-dione, 0.45 gram of anhydrous potassium acetate and twenty milliliters of acetone was heated at its refluxing temperature for a period of five hours. The mixture was then cooled and poured into water and extracted with methylene chloride. The methylene chloride extract was dried and poured over a column of 25 grams of Florisil synthetic magnesium silicate. The column was developed with Skellysolve B hexane hydrocarbons containing increasing portions of acetone. The Skellysolve B plus ten percent acetone eluate contained 6amethyl-9(1l)-oxido-17a-hydroxy-l,4-pregnadiene-3,ZO-dione.

A solution of one gram of 6a-methyl9(11)-oxido-17ahydroxy-l,4-pregnadiene-3,20-dione' was dissolved in fifty milliliters of methylene chloride and thereto was added five milliliters of 48 percent hydrofluoric acid and 0.5 milliliter of 71 percent perchloric acid. The mixture was stirred vigorousy for six hours and then poured into an excess of cold aqueous five percent sodium bicarbonate solution. The methylene chloride layer was separated, dried with anhydrous sodium sulfate and then poured over a column of 100 grams of Florisil synthetic magnesium silicate.

percent acetone were recrystallized from acetone and Skellysolve B hexanes to give pure ot-II1BthY1-9u-fl1l0l'0- 1119,17ot-dihydroxy-1,4-pregnadiene-3,20-dione of melting point 292 to 303 degrees centigrade.

. Following the procedure described in Example 6, but substituting other 6ot-alkylor 6u-aryl-11fi,17u-dihydroxy- 1,4-pregnad-iene-3,20-diones for the 6a-methyl-1 113,170:- dihydroxy-1,4-pregnadiene-3,20-dione wherein the alkyl radical is ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,

hexyl, or an aryl, such as phenyl, or the like, results in The column was developed with Skelly-' solve B hexanes and acetone, the fractions containing ten 1 nene-3,20-dione alkyl group is ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, or aryl such as phenyl, or the like.

-In the same manner as shown-with ther6a-epimersthe 6,8-epimers may be used as starting materials for the above Example 6.

EXAMPLE 7 6 a methyl c fluoro -11 13,170: dihydroxy-L4-pregnadiene-3,20 di0ne from- 6a-m'ethyl-9a-flu0r0J 15,] 7adihydroxy-4-pregnene-3,20-di0ne Six -milliliter. portions of a medium in 250-mil1iliter Erlenmeyer flasks containing one percent glucose,

two percent corn steep liquor (60 percent solids). and

tap water was adjusted to a pH of 5.9. This medium was sterilized for 45 minutes at fifteen pounds per square inch pressure and inoculated'with a one to two day,

liters of an antifoam (a mixture of lard oil and octadecanol). The fermentor was placed into the water bath, adjusted to 28 degrees centigrade, and the contents stirred (300 R. P. M.) and aerated (0.5 1. air/10 1. beer). growth developed and the acidity rose to pH 6.7, two grams of 6a-methyl-9a-fluoro-1lfi,17a-dihydroxy-4-preg- (copending application Serial No. 659,754, filed May 17, 1957) plus one'gram of 3- ketobisnor-4-cholen-22-al dissolved in milliliters of dimethylformamide, was added and the incubation (conversion) carried out at the same temperature and aeration for 24 hours as used during the incubation. The mycelium was filtered OE and the steroidal material was extractedwith methylene chloride, the methylene chloride extracts evaporated to dryness, and the resulting residue chromatographed over a Florisil anhydrous magnesium silicate column. 7 The column was packed with 200 grams of Florisil and was developed with five 400-milliliter fractions each of methylene chloride, I

Skellysolve B hexane-acetone mixtures of 9:1, 8:2, 7 :3 1:1, and methanoL- The fraction eluted with Skellysolve B hexane-acetone (7:3) was evaporated and recrystallized from acetone to give 6a-methyl-9a-fluoro- 11 3,17a-dihydroxy-1,4-pregnadiene-3,20-dione of melting point 292 to 303 degrees centigrade;

It is to be understood that the invention is not to be limited to the exact details of operation or exact com 3,20-dione and 6.-methyl-9afluoro -17u-hydroxy1,4-pregnadiene-3 ,1 1,20-trione.

diene-3,20-dione.

3. '6u-methyl-9u-fluoro-17a-hydroxy 1,4 pregnadiene- 3,11,20-trione.

References Cited the file of this patent UNITED STATES PATENTS Fried Sept. 18, 1956 Nussbaum Nov. 26, 1957 OTHER REFERENCES Spero et al.: JACS, 78, December 5, 1956,.p-ages 6213, 6214. v 1

After 17 hours of incubation, when a good 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 6-METHYL-9A-FLUORO-11B,17A-DIHYDROXY-1,4 - PREGNADIENE3,20-DIONE AND 6-METHYL-9A-FLUORO-17A-HYDROXY-1,4-PREGNADIENE-3,11,20-TRIONE. 